Regeneration in response to injury is limited to select tissues in adult mammals. The default response to injury in most other tissues involves the processes of inflammation and scar tissue formation (i.e., repair). The microenvironment of the wound plays an important role in determining regeneration versus scar in adult mammals. In species capable of regenerating complex tissues, stem cells recruited to the wound microenvironment promote a process known as epimorphic regeneration. Biologic scaffolds composed of porcine derived extracellular matrix (ECM) have successfully been used in over one million human patients to create a wound microenvironment that promotes site-specific, non-inflammatory repair of a variety of soft tissues. Implantation of an ECM scaffold following tissue injury results in rapid degradation, release of bioactive peptides, local macrophage polarization, and endogenous stem cell recruitment. The mechanisms underlying ECM mediated stem cell recruitment in vivo are well not understood, but may partially be mediated by molecules released following ECM degradation. Polarized macrophages are also capable of recruiting stem cells in vitro, but their contribution to endogenous stem cell recruitment in vivo is not well understood. The overall goal of the present study is to investigate: (1) role of ECM degradation in stem cell recruitment in vitro and in vivo, (2) the role of ECM degradation on macrophage polarization in vitro and in vivo, and (3) the relative contributions of ECM degradation and polarized macrophages upon endogenous stem cell recruitment in vivo. The findings of the present study further inform us on the on the role of the innate immune system in promoting tissue regeneration, and it will serve as the foundation of future studies to further investigate the mechanisms underlying interaction between extracellular matrix components, the innate immune system, and endogenous stem cells. PUBLIC HEALTH RELEVANCE: THE RELATION OF OUR STUDIES TO PUBLIC HEALTH: The findings from these studies will further our understanding of the respective contributions of the innate immune system and ECM scaffold degradation in promoting functional tissue regeneration. It will serve as the foundation of future avenues of investigation that will aim to develop more targeted therapies for promoting tissue regeneration and functional recovery following injury in humans.